PDBsum entry 4rxs

Hydrolase

PDB id: 4rxs

Contents

Protein chains

481 a.a.

Ligands

GTP ×2

TTP ×4

Metals

_MG ×2

Waters ×407

PDB id:

4rxs

Name:

Hydrolase

Title:

The structure of gtp-dttp-bound samhd1

Structure:

Deoxynucleoside triphosphate triphosphohydrolase samhd1. Chain: a, b. Synonym: dntpase, dendritic cell-derived ifng-induced protein, dcip, monocyte protein 5, mop-5, sam domain and hd domain-containing protein 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: samhd1, mop5. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.20Å R-factor: 0.195 R-free: 0.222

Authors:

C.F.Zhu,W.Wei,X.Peng,Y.H.Dong,Y.Gong,X.F.Yu

Key ref:

C.F.Zhu et al. (2015). The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP. Acta Crystallogr D Biol Crystallogr, 71, 516-524. PubMed id: 25760601 DOI: 10.1107/S1399004714027527

Date:

11-Dec-14 Release date: 11-Mar-15

Protein chains

Q9Y3Z3  (SAMH1_HUMAN) -  Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 from Homo sapiens

Seq: 626 a.a.

Struc: 481 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.5.- - ?????

DOI no: 10.1107/S1399004714027527

Acta Crystallogr D Biol Crystallogr 71:516-524 (2015)

PubMed id: 25760601

The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP.

C.F.Zhu, W.Wei, X.Peng, Y.H.Dong, Y.Gong, X.F.Yu.

ABSTRACT

SAMHD1 is the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is elegantly regulated by the self-sensing ability of SAMHD1 through a novel activation mechanism.